New STAT1-us quo? Novel STAT1 variants cause Mendelian susceptibility to mycobacterial disease

Patients with Mendelian susceptibility to mycobacterial disease (MSMD) are susceptible to atypical mycobacteria such as BCG, other environmental mycobacteria, and Salmonella. Here, we identified 8 patients from 4 families with MSMD due to STAT1 variants, including 3 new to Japan. When we see BCG-associated morbidity, we should suspect MSMD. Credit: Department of Child Health and Development, TMDU. Journal of Clinical Immunology (2022). DOI: 10.1007/s10875-022-01396-1

Usually the scariest part of childhood vaccinations, for both kids and parents, are the needles. In rare cases, however, vaccines can have unexpected negative effects, and the secret lies in our genes.

In a study recently published in the Journal of Clinical Immunologyresearchers from Tokyo Medical and Dental University (TMDU) have revealed three previously unknown variants that can cause a severe reaction to a normal childhood vaccine.

In countries where TB is common, children are often given the Bacille Calmette-Guérin (BCG) vaccine to protect them against infection. Some cases, however, show an unexpected negative reaction to the BCG vaccine, due to a condition known as Mendelian susceptibility to mycobacterial disease (MSMD). The BCG vaccine in children with MSMD can cause swollen lymph nodes, inflammation of bone tissue, and abscesses.

“Adverse reactions to the BCG vaccine are known to be associated with inherited variants of genes involved in the immune response,” says the study’s lead author, Rintaro Ono. “So when we encountered four pediatric patients who showed signs of mycobacterial disease after BCG vaccination, we analyzed their genome to determine which mutations were responsible for this reaction.”

To do this, the research team took blood samples from the children and their immediate parents and sequenced their genomic DNA to identify variants in genes linked to immunity. They then tested the effects of the variants identified in the laboratory to determine the functional consequences of the variants.

“The results were somewhat unexpected,” says lead author Hirokazu Kanegane. “While the variants we found were in a gene called STAT1, which is often mutated in patients with MSMD, three of the four variants we identified had never been seen before.”

Functional analysis of these three new variants demonstrated that they caused the STAT1 protein to lose function, rendering it unable to activate an appropriate immune response to the vaccine. Importantly, the variants show a dominant negative, which means that the products of these mutated genes prevent the wild-type (also known as the wild-type) gene products from carrying out their normal activities, the all in the same cell.

These results suggest that heterozygous dominant negative variants of STAT1 could be a common cause of MSMD in Japanese patients. Because early symptoms of MSMD (such as fever) are common in children, but may be severe or prolonged in patients with MSMD, it is important to closely monitor these patients after BCG vaccination. Careful monitoring and evaluation of STAT1 variants, such as those identified in this study, may allow these patients to be diagnosed and treated earlier.

Provided by Tokyo Medical and Dental University